ABT-869, a multi-targeted tyrosine kinase inhibitor, in combination with rapamycin is effective for subcutaneous hepatocellular carcinoma xenograft.
OBJECTIVE
Receptor tyrosine kinase inhibitors (RTKIs) and mTOR inhibitors are potential novel anticancer therapies for HCC. We hypothesized that combination targeted on distinctive signal pathways would provide synergistic therapeutics.


METHODS
ABT-869, a novel RTKI, and rapamycin were investigated in HCC pre-clinical models.


RESULTS
Rapamycin, but not ABT-869, inhibited in vitro growth of Huh7 and SK-HEP-1 HCC cells in a dose dependant manner. However, in subcutaneous Huh7 and SK-HEP-1 xenograft models, either ABT-869 or rapamycin can significantly reduce tumor burden. Combination treatment reduced the tumors to the lowest volume (95+/-20mm(3)), and was significantly better than single agent treatment (p<0.05). Immunohistochemical staining of tumor shows that ABT-869 potently inhibits VEGF in HCC in vivo. In addition, the MAPK signaling pathway has been inhibited by significant inhibition of phosphorylation of p44/42 MAP kinase by ABT-869 in vivo. Rapamycin inhibits phosphorylation of p70 S6 kinase and 4E-BP-1, downstream targets of mTOR, and decreases VEGF. Combination treatment showed synergistic effect on expression levels of p27 in vivo. Dramatic inhibition of neo-angiogenesis by ABT-869 was also demonstrated.


CONCLUSIONS
HCC could potentially be treated with the combination treatment of ABT-869 and rapamycin. Clinical trials on combination therapy are warranted.
Jasinghe
Viraj J
VJ
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, Singapore 119074, Singapore.
Xie
Zhigang
Z
Zhou
Jianbiao
J
Khng
Jiaying
J
Poon
Lai-Fong
LF
Senthilnathan
Palaniyandi
P
Glaser
Keith B
KB
Albert
Daniel H
DH
Davidsen
Steven K
SK
Chen
Chien-Shing
CS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004359:Drug Therapy, Combination; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007191:Indazoles / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D020123:Sirolimus / Q000494:pharmacology*; D050151:Subcutaneous Fat; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D007166:Immunosuppressive Agents; D007191:Indazoles; D010671:Phenylurea Compounds; D010982:Platelet-Derived Growth Factor; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C513486:linifanib; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus